The Circadian Gene Clock Regulates Bone Formation Via PDIA3

Area of Science:

• Molecular Biology
• Chronobiology
• Bone Biology

Background:

• Circadian rhythm regulates clock-controlled genes (ccgs), impacting physiological processes.
• Disruptions in circadian rhythm are linked to diseases like cancer and aging.
• Bone remodeling is influenced by circadian rhythm, but the underlying molecular mechanisms involving the Clock gene are unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which the circadian gene Clock regulates bone remodeling.
• To investigate the role of PDIA3 in Clock-mediated bone formation and apoptosis.

Main Methods:

• Utilized Clock mutant mice to assess bone density and apoptosis.
• Employed luciferase and ChIP assays to confirm Pdia3 as a ccg and Clock's transcriptional regulation.
• Investigated the effects of forced Pdia3 or Clock expression and PDIA3 ablation via RNA interference.

Main Results:

• Clock mutant mice showed reduced bone density and increased apoptosis.
• Confirmed Pdia3 as a ccg, with Clock activating its transcription via E-box promoter binding.
• Forced expression of Pdia3 or Clock rescued osteogenic disorders and inhibited apoptosis.
• PDIA3 ablation blocked the compensatory effect of Clock overexpression in osteoblasts.

Conclusions:

• The core circadian gene Clock regulates bone formation through transcriptional control of the 1,25-dihydroxy-vitamin D3 receptor PDIA3.
• This study reveals a novel molecular pathway linking circadian rhythm to bone metabolism.